Hearing impairment has a major impact on affected individuals. It can profoundly influence communication, language acquisition, speech, cognitive skills and psychosocial development. More than 60 percent of the cases of profound early-onset deafness are caused by genetic factors, which in most cases are due to single gene mutations. Nonsyndromic hearing impairment (NSHI) is the most heterogeneous trait known. Thus far, over 90 genes have been localized for NSHL and 35 genes have been identified. The goals of this project are to continue to develop a resource of families with NSHL, map novel NSHL loci, refine the genetic regions for known NSHL loci and identify novel NSHL genes. Families have been ascertained from Switzerland, Jordan, Turkey, Pakistan and the United States. Currently, additional families are being ascertained in Pakistan, Jordan and the USA. For the families that have been ascertained, genome scans and fine mapping is carried to establish linkage and map the locus segregating in the family to the smallest possible genetic region. The genes responsible for low frequency NSHI (WFS1) and a form of high frequency NSHI (ACTG1) have been identified in two of the USA families. This study has also identified a number of novel loci (DFNA23, DFNA24, DFNB35, DFNB38, DFNB39, DFNB42, DFNB43, DFNB44 and DFNB45) for which the genes are currently unknown. In addition, for other families linkage has been established and the genetic region has been reduced (e.g. DFNB13, DFNB19) for known NSHI loci where the gene has not yet been identified. Gene identification is conducted in regions where a gene has not been identified to date by screening genes that map to the same physical region as the NSHI locus of interest. Sequencing will first be performed on those genes that are believed to be the strongest candidates. A gene will be considered a good candidate if it belongs to a class of genes that have previously been implicated in the hearing impairment phenotype, has a potential function in the role of hearing and/or is expressed within the cochlea based upon RT-PCR experiments and from information available in public databases. The importance of obtaining good clinical data is stressed in order to develop phenotype/genotype relationships. The study will also yield important information on the public health impact of certain genes/mutations within various populations. Technology has been developed at the Baylor Human Genome Sequencing Center to facilitate the sequencing of a large number of genes in a cost- and time-efficient manner and has been implemented in this study. Identification of novel genes for NSHI will aid in understanding the function of genes controlling the mechanism of hearing, which will in the future facilitate the development of intervention strategies to prevent and treat hearing impairment.